Infection with Mycobacterium tuberculosis (Mtb) increases AIDS-related deaths in people living with HIV-1. Approximately, 99% of deaths due to HIV-Mtb coinfection take place in developing countries such as India. Furthermore, evolution of genetically and functionally distinct clinical strains of HIV and Mtb strains further fuel the HIV-B epidemic. Despite this, there remains limited understanding of mechanisms of HIV mediated exacerbation of TB infection. In the co-infected individual, both Mtb and HIV potentiate one another, promoting immunologic dysfunction, metabolic disorder and premature death. Various lines of evidence implicate HIV accessory proteins (Tat, Nef, Vpu) in orchestrating major alterations in the host cellular homeostasis processes such as redox balance, membrane potential, and central metabolism resulting in immune dysfunction, virus replication and progression to AIDS. Furthermore, clade-specific genetic diversity within HIV proteins distinctly manipulates host redox response and immune deregulation. Similarly, redox signaling also plays an important role in modulating survival and virulence of Mtb in vivo. It has been demonstrated that the major cellular antioxidant glutathione (GSH) either directly or indirectly modulates innate and adaptive immune mechanisms to control Mtb infection. Interestingly, HIV infected individuals demonstrate either depletion or oxidation of serum GSH levels. HIV-mediated changes in host redox physiology likely influences the pathogenesis of Mtb and has not been addressed in the HIV-TB field. In addition, the effect of distinct genotypic and phenotypic variations within various strains of HIV and Mtb on host redox homeostasis remains uncharacterized. We believe that a significant bottleneck exists in investigating redox-based signaling events during HIV-TB coinfection, primarily because of lack of non-invasive tools to dynamically measure HIV-induced redox stress at the cellular and sub- cellular levels and the absence of appropriate animal models. To address this, we propose to utilize a novel genetically encoded green fluorescent protein based redox bioprobe, Grx1-roGFP2 that allows us to determine specific, quantitative, and dynamic and compartment specific redox changes associated with HIV-TB coinfection. Furthermore, we plan to creatively use HIV-1 transgenic mice to study how HIV-induced redox changes modulate survival and persistence of Mtb in vivo. One of the major strengths of the proposal is the use of Indian clinical isolates of HIV and Mtb to dissect redox signaling events associated with HIV-TB coinfections. We believe that our study will provide significant insight into redox processes underlying HIV-TB dual infection which will lead to identification of novel drug targets and organelle-specific antioxidant therapy and ultimately to better therapeutic interventions for individuals afflicted with these co-morbidities.